Research Papers:

Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis

Marta Anna Kowalik _, Giulia Guzzo, Andrea Morandi, Andrea Perra, Silvia Menegon, Ionica Masgras, Elena Trevisan, Maria Maddalena Angioni, Francesca Fornari, Luca Quagliata, Giovanna Maria Ledda-Columbano, Laura Gramantieri, Luigi Terracciano, Silvia Giordano, Paola Chiarugi, Andrea Rasola and Amedeo Columbano

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Oncotarget. 2016; 7:32375-32393. https://doi.org/10.18632/oncotarget.8632

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Marta Anna Kowalik1,*, Giulia Guzzo2,*, Andrea Morandi3,*, Andrea Perra1, Silvia Menegon4, Ionica Masgras2, Elena Trevisan2, Maria Maddalena Angioni1, Francesca Fornari5, Luca Quagliata6, Giovanna Maria Ledda-Columbano1, Laura Gramantieri5, Luigi Terracciano6, Silvia Giordano4, Paola Chiarugi3, Andrea Rasola2, Amedeo Columbano1

1Department of Biomedical Sciences, University of Cagliari, 09124, Cagliari, Italy

2Department of Biomedical Sciences, University of Padova, 35122, Padova, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Firenze and Tuscan Tumor Institute, Florence, Italy

4Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo, Italy

5Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi, 40138, Bologna, Italy

6Molecular Pathology Division, Institute of Pathology, University Hospital of Basel, CH-4003, Basel, Switzerland

*These authors have contributed equally to this work

Correspondence to:

Amedeo Columbano, email: [email protected]

Andrea Rasola, email: [email protected]

Keywords: TRAP1, NRF2, HCC, oxidative phosphorylation, pentose phosphate pathway

Received: January 15, 2016    Accepted: March 28, 2016    Published: April 7, 2016


Metabolic changes are associated with cancer, but whether they are just bystander effects of deregulated oncogenic signaling pathways or characterize early phases of tumorigenesis remains unclear. Here we show in a rat model of hepatocarcinogenesis that early preneoplastic foci and nodules that progress towards hepatocellular carcinoma (HCC) are characterized both by inhibition of oxidative phosphorylation (OXPHOS) and by enhanced glucose utilization to fuel the pentose phosphate pathway (PPP). These changes respectively require increased expression of the mitochondrial chaperone TRAP1 and of the transcription factor NRF2 that induces the expression of the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD), following miR-1 inhibition. Such metabolic rewiring exclusively identifies a subset of aggressive cytokeratin-19 positive preneoplastic hepatocytes and not slowly growing lesions. No such metabolic changes were observed during non-neoplastic liver regeneration occurring after two/third partial hepatectomy. TRAP1 silencing inhibited the colony forming ability of HCC cells while NRF2 silencing decreased G6PD expression and concomitantly increased miR-1; conversely, transfection with miR-1 mimic abolished G6PD expression. Finally, in human HCC patients increased G6PD expression levels correlates with grading, metastasis and poor prognosis. Our results demonstrate that the metabolic deregulation orchestrated by TRAP1 and NRF2 is an early event restricted to the more aggressive preneoplastic lesions.

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